.alpha.-Aryl carboxylic acids are well known non-steroidal anti-inflammatory (NSAI) drugs. An example is ibuprofen (Formula 1) which is typically a racemic mixture of the S(+)- and R(-)-enantiomers. ##STR1##
Studies have indicated that the S(+)-isomer is more pharmacologically active than the R(-)-isomer, see, for Example, A. Avgerinos et al, Chirality, Vol. 2, 249 (1990). Attempts have been made recently to isolate the S(+)-isomer from the racemic mixture.
U.S. Pat. No. 5,015,764 (Assignee: Ethyl Corp.) discloses a process whereby the triethylamine salt of racemic ibuprofen is treated with chiral .alpha.-methyl-benzylamine (MBA). The MBA salt of one isomer of ibuprofen separates as crystals and is filtered off. The triethylamine salt of the other isomer is isolated from the filtrates, is separately racemized, and is then treated again as described above.
U.S. Pat. No. 4,994,604 (Assignee: Merck & Co.) teaches S-lysine for the resolution of racemic ibuprofen. Racemic ibuprofen and S-lysine are combined in equimolar quantities in a solvent system, such as ethanol:water so that the solution is supersaturated in both R, S and S, S salts. The solution is first aged at around 30.degree. C., and then seeded at around 25.degree. C. with a fairly large amount of S-ibuprofen-S-lysinate. This allows the S-ibuprofen-S-lysinate from the racemate mixture to crystallize out. The mother liquor, after filtration, is seeded again to precipitate additional S-salt. Repetition of this process gives the S-ibuprofen-S-lysinate as crystals, and leaves the R-salt in the solution, thus allowing a recovery of 50% of the original amount of the racemic ibuprofen as S-ibuprofen lysinate salt.
U.S. Pat. No. 5,189,208 (Assignee: Ethyl Corporation) discloses a process for obtaining a substantially pure enantiomer of ibuprofen. The process utilizes first an enantiomerically enriched mixture of ibuprofen obtained from kinetic resolution, diastereomeric crystallization, or asymmetric synthesis processes. This enriched mixture is dissolved in a solvent and solid racemic ibuprofen is separated, leaving a mother liquor comprising the solvent and the enriched enantiomer substantially free of the other enantiomer.
Other prior art references which are pertinent include U.S. Pat. Nos. 3,43 1,295; 4,752,417; 4,994,604; British Patent Specification No. 899,023; and pending U.S. patent application Ser. No. 07/649,782, filed Jan. 31, 1991 (A. Bhattacharya et al.).
All of these prior art references are submitted pursuant to 37 CFR 1.56, 1.97, and 1.98. These references, patent applications, and patents are incorporated herein by reference in their entirety.
Other methods such as enzymatic resolution and chromatography have also been suggested for resolution. The disadvantage with such processes is that they are time-consuming, and the yields are low.
While resolution of racemic mixtures is known, generally such processes lead to yields of a maximum 50% of one isomer, and 50% of the other isomer. In order to get higher yields of one isomer, the other isomer, after isolation, must be separately racemized to eventually isolate more of the desired isomer. Such processes generally employ conditions that are so different from the resolution step that the two are incompatible for efficient recycle. Because optically active .alpha.-aryl carboxylic acids and their salts have greater commercial value than racemic acids and their salts, there is a growing interest in finding improved methods to selectively crystallize such salts from solutions containing the racemic acid and a chiral amine.